The present invention relates generally to pharmaceutical compositions containing peptides having angiostatic properties and more particularly to pharmaceutical compositions of tryptophan-containing dipeptides and methods of use thereof.
Neovascularization, the genesis of new blood vessels, is triggered early in embryogenesis and also during wound healing, tissue remodeling and probably in the normal course of maintenance of the vascular system. Processes involved in neovascularization include at least endothelial cell and pericyte activation; basal lamina degradation; migration and proliferation of endothelial cells and pericytes; formation of a new capillary vessel lumen; appearance of pericytes around the new vessels; development of a new basal lamina; capillary loop formation; persistence of involution with differentiation of the new vessels; capillary network formation; and, eventually, of the network organization into larger microvessels.
Certain cytokines are known to down-regulate neovascularization, including interleukin-12 (IL-12), transforming growth factor-.beta. (TGF-.beta.), interferon-.alpha. (IFN-.alpha.) and platelet factor 4 (PF-4). However, clinical experience with cytokine therapy has proven problematic due to the toxicity of certain of these compounds.
There are a number of pathologic conditions in which angiogenesis either plays a role in or is involved directly in different sequelae of the disease. These include, for example, neovascularization of tumors in cancer; creation of hemangeomas; neovascularization associated with various liver diseases; angiogenic dysfunction related to an excess of hormone; neovascular sequelae of diabetes; neovascular sequelae to hypertension; neovascularization in post-recovery cerebrovascular accident; neovascularization due to head trauma; neovascularization in chronic liver infection; restenosis following angioplasty; and neovascularization due to heat or cold trauma.
While angiogenesis is undoubtedly required for maintenance of a healthy vascular system, clinical medicine would appreciate the availability of a non-toxic treatment for temporarily down-regulating neovascularization, i.e., inducing a temporary angiostasis.